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To the Editor:

The role of niacin in the era of widespread statin use has been called into question by 2 recent clinical trials, AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health) and HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events), indicating no added benefit when niacin was added to standard low-density lipoprotein (LDL) reduction therapy with simvastatin and ezetimibe (1).

Mass-based assessment of high-density lipoprotein cholesterol (HDL-C) levels may not fully capture substantial variability in HDL functional properties. Cholesterol efflux capacity, a marker of the ability of HDL to accept cholesterol from macrophages and thus facilitate reverse cholesterol transport, served as a stronger predictor of atherosclerotic burden than HDL-C levels in 2 independent cohorts (2). This inverse association with coronary disease prevalence was confirmed using a related assay in 2 additional cohorts by Li et al. (3); an unexpected direct association with prospective events awaits further confirmation. Furthermore, the HDL inflammatory index, a surrogate for HDL's antioxidant capacity, was impaired in patients in the midst of an acute coronary syndrome (4).

We conducted a study designed to assess the impact of niacin added to statin therapy on HDL-C levels, cholesterol efflux capacity, and the HDL inflammatory index. Samples were derived from a previously described randomized controlled trial (NCT00307307) (5). In brief, patients with carotid atherosclerosis were randomized to simvastatin 20 mg daily plus either placebo or extended-release (ER) niacin, titrated up to 2 g daily. HDL-C levels and functional parameters were assessed at baseline and after 6 months of therapy.

Cholesterol efflux capacity was quantified using a previously validated cell-based assay that quantifies the ability of apolipoprotein B–depleted plasma to accept radiolabeled cholesterol from J774 macrophages ex vivo (3). Similarly, the HDL inflammatory index measured the capacity of apolipoprotein B–depleted plasma to inhibit the oxidation of purified LDL-C (4). All assays were performed in duplicate. To control for interassay variation, sample values were normalized to a pooled plasma control run on each plate.

The association between HDL functional parameters and baseline biomarkers was assessed using Pearson correlation coefficients. Paired Student t tests were used to analyze the effect of pharmacotherapy on HDL parameters. These changes were compared with placebo using an analysis of covariance test using the patient's baseline value and treatment group as covariates.

Baseline and 6-month plasma samples were available in 39 patients, 19 in the simvastatin plus ER niacin group and 20 who received simvastatin plus placebo. Fifteen of the 19 patients (79%) randomized to receive ER niacin achieved the target dose of 2 g daily, with a mean achieved daily dose of 1.8 g. Baseline characteristics were similar to those of the study population as a whole and revealed no significant difference between treatment groups. The mean age of study participants was 71 years; 64% were male, 26% had diabetes, 69% had hypertension, 23% had a history of coronary artery disease, and 67% were taking a statin at baseline. Average total cholesterol was 185 mg/dl, with mean HDL-C and LDL-C of 46 mg/dl and 116 mg/dl, respectively. Median values for triglycerides and C-reactive protein were 135 mg/dl and 1.4 mg/l, respectively.

Substantial variation was noted across study participants in HDL functional parameters. Mean normalized cholesterol efflux capacity was 0.95, with a range of 0.57 to 1.54; average HDL inflammatory index value was 1.15, with range of 0.70 to 2.81. The mean coefficient of variation was 5.5% for cholesterol efflux capacity and 4.3% for HDL inflammatory index.

The impact of the 2 treatment regimens on HDL-C levels and functional metrics are displayed in Figure 1. As expected, the addition of niacin therapy led to a robust increase in average HDL-C from 46 to 57 mg/dl (p = 0.001 compared with baseline; p = 0.001 compared with placebo). However, no change was noted in either cholesterol efflux capacity (mean change −1%; 95% confidence interval: −11% to 10%) or HDL inflammatory index (mean change 9%; 95% confidence interval: −6% to 24%).

These results thus indicate the feasibility of using 2 complementary assays of HDL function in a small drug study. The addition of niacin to statin therapy led to favorable changes in patients' lipid profiles without a demonstrable effect on HDL functionality, thus providing one potential mechanistic hypothesis for the disappointing results in recent clinical trials.

The strengths of this study include its randomized, placebo-controlled, prospective design and the use of robust assays with previous relationship to cardiovascular disease phenotypes. Limitations include small size, although the matched-pairs statistical plan afforded 80% power to detect a 13% and 15% improvement in cholesterol efflux capacity and HDL inflammatory index, respectively. Furthermore, any potentially beneficial effect of niacin via LDL-C or lipoprotein(a) reduction would not have been detected owing to the HDL specificity of the assays. (Carotid Atherosclerosis Regression at Magnetic Resonance Assessment; NCT00307307).

Footnotes

Please note: The study was approved by the University of Pennsylvania institutional review board. The study was supported by investigator-initiated grants from Merck Pharmaceuticals (Whitehouse Station, New Jersey) and KOS Pharmaceuticals, now Abbott Pharmaceuticals (Abbott Park, Illinois). The companies had no influence on study design, analysis, or abstract preparation. Dr. Rader is the founder of VascularStrategies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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